This is a 371 of PCT/GB99/01266 filed May 11, 1999,
The present invention relates to the treatment and prevention of vascular proliferative disorders such as restenosis following coronary angioplasty.
A major cause of cardiovascular disease is blockage of an artery as a result of atherosclerosis. This is especially serious in the coronary artery, but also affects arteries in other parts of the body including the head and limbs. Balloon angioplasty is a highly effective treatment for restoring blood flow through an atherosclerotic artery. It involves feeding a balloon to the affected artery and then inflating it to create an enlarged channel. However there is a relatively high rate of relapse following balloon angioplasty: 30-50% of patients experience a re-growth of tissue within the angioplastied artery that can re-occlude the lumen (a vascular proliferative condition known as restenosis), necessitating further surgery. Restenosis is due to the growth of smooth muscle-like cells within the lumen to form an abnormal lining (the neointima) that occludes the lumen of the artery.
The cell signalling molecule ras is a key molecule in the regulation of cell proliferation through the MAP kinase pathway. Correct function of ras depends upon its location at the cell membrane, which is achieved by linking it to a farnesyl moiety, that inserts specifically in the membrane. This farnesylation step is carried out by the enzyme farnesyl transferase, and thus inhibitors of farnesyl transferase will prevent ras function.
It has previously been proposed in WO97/00252 that certain tricyclic inhibitors of farnesyl transferase enzyme (FTIs) can be used in the treatment of a wide variety of proliferative diseases such as cancer, psoriasis, and restenosis. The treatments disclosed simply comprise conventional treatment regimens using oral or parenteral administration of various formulations such as tablets, capsules, liquids, pastes, gels etc and including sustained release formulations. Such treatments of proliferative diseases are normally used over extended periods of weeks or months. Given the fundamental importance of cell growth and maintenance to good health, it is not at all surprising that such treatments are normally associated with serious side effects which have an important effect on restricting the use thereof.
It is an object of the present invention to avoid or minimize one or more of the above disadvantages.
It has now very surprisingly and unexpectedly been found that a single brief local application of a farnesyl transferase inhibitor, for example, a farnesyl analogue, to the vascular wall substantially contemporaneously with a surgical procedure for removing a vascular occlusion, can substantially prevent restenosis of the vascular passage without the need for further subsequent treatments.
Without in any way wishing to restrict the scope of the present invention it is believed that the use of the farnesyl transferase inhibitors in this way inhibits the proliferation of vascular smooth muscle cells due to blocking of the MAP kinase pathway by preventing membrane incorporation of ras.
Thus in one aspect the present invention provides a farnesyl transferase inhibitor for use in the preparation of a medicament for local application to the vascular wall so as to substantially prevent restenosis of the vascular passage.
In another aspect the present invention provides a method of prophylaxis of restenosis comprising administration of an effective dosage of a farnesyl transferase inhibitor to the vascular wall substantially contemporaneously with a surgical procedure for removing a vascular occlusion, for example angioplasty.
It is a particular advantage of the present invention that restenosis can be substantially prevented, at least for extended periods of time of several weeks or months, if not indefinitely, following a single treatment, which is moreover localised to the affected area. Thus the risk of any possible side effects is substantially avoided or at least very substantially reduced when compared with conventional treatments of proliferative diseases.
Suitable farnesyl transferase inhibitors known in the art include the known Farnesyl Transferase Inhibitors FPTII and FPTIII which are commercially available from Calbiochemxe2x80x94Nova Biochem UK of Beeston, Nottingham, England (Manne V, et al (1995) xe2x80x9cRas farnesylation as a target for anti-tumour agents: potent and selective farnesyl diphosphate analogue inhibitors of farnesyltransferaseoxe2x80x9d, Drug Development Research 34, 121-137) and which have the following formulae: 
Other compounds which may be used in accordance with the present invention include arglabin which is 1,10-Epoxy- 3,11(13)-guaiadien-12,6-olide including stereoisomers thereof and especially the naturally occuring stereoisomer which is believed to have the structural formula 
and perillol, also known as Perillyl alcohol which is 1-Hydroxymethyl-4-isopropenylcyclohexene (including both R- and S- enantiomeric forms of this compound), as well as glycosidic compounds such as those disclosed in WO97/04788, the contents of which disclosure are incorporated herein by reference to said publication. In more detail, said glycosidic compounds are compounds of formula (I): 
wherein R1 and R2 are independently selected from H, OH, 
and related esters thereto;
R3 is selected from OH, 
xe2x80x83and related esters thereto;
R1 is selected from C6-C12 saturated or unsaturated monocyclic or polycyclic aliphatic ring systems optionally substituted by C1-C6 alkyl, H, OH, xe2x95x90CH2 or C1-C3 alkyl carboxyloxy or R1 represents a C1-C6 straight- or branched-chain alkalene group substituted with such a ring system;
R5 is selected from xe2x80x94CH3, xe2x80x94CHO, xe2x80x94COOH and xe2x80x94CH2 OH and related esters and ethers derived therefrom;
R6 is selected from xe2x80x94OH, 
In accordance with the present invention, the farnesyl transferase inhibitors are administered substantially contemporaneously with the surgical procedures including immediately before and/or during and/or after the surgical procedure. Most conveniently administration is effected as soon as practicable after completion of the surgical procedure, typically from 1 to 60 minutes after completion of the procedure. The duration of the procedure may depend on the nature of the farnesyl transferase inhibitor used and/or of the formulation used including the concentration of the farnesyl transferase inhibitor, the nature of the vehicle, etc. Typically the farnesyl transferase inhibitor formulation is applied to the vascular wall for from 5 to 60 minutes, conveniently from 10 to 30 minutes, for example about 15 minutes.
Advantageously the area of vascular wall undergoing treatment is substantially isolated from the fluid normally flowing therethrough, during the course of application of the farnesyl transferase inhibitor formulation thereto. This may conveniently be achieved by means of a conventional dispatch catheter which defines an annular chamber between the vascular wall and the outside of a central by-pass passage through which normal vascular fluid flow can be maintained. The farnesyl transferase inhibitor formulation may thus be brought into direct contact with the vascular wall by introduction into the annular chamber without the need for interrupting the normal vascular fluid flow. This method also has the advantage of substantially restricting exposure of the patient to the formulation to only the particular area requiring treatment thereby further restricting the possibility of undesirable side effects from the treatment. In principle once the annular chamber has been filled with the liquid formulation this would simply be held therein for the required treatment period following which it may be withdrawn. In practice a small amount of leakage from the chamber into the vascular flow may be experienced so that it would normally be desirable to continue infusion of formulation at a slow rate e.g. from 10 to 1000 xcexcl per minute, e.g. 200 xcexcl per minute, during the treatment period to compensate for leakage losses.
In general the farnesyl transferase inhibitors are formulated with common pharmaceutical carriers and excipients into liquid formulations suitable for use in parenteral, especially intravenous, administration. Suitable liquid formulations include solutions, suspensions and emulsions, e.g. water or aqueous propylene glycol solutions. In general the formulations are substantially physiologically isotonic. The formulations may contain from 5xc3x9710xe2x88x922% to 5xc3x9710xe2x88x928% w/v of the farnesyl farnesyl transferase inhibitor, preferably from 5xc3x9710xe2x88x923% to 5xc3x9710xe2x88x927% w/v, advantageously from 5xc3x9710xe2x88x924% to 5xc3x9710xe2x88x926%w/v.
Typically there would be used a formulation with a farnesyl transferase inhibitor concentration of around 0.5 mg/l (5xc3x9710 xe2x88x925%W/V). Given a typical treatment volume of the order of 3 ml this would typically correspond to a total dosage rate of 2.5 ug per kg bodyweight of the patient. In general the farnesyl transferase inhibitors are administered at a dosage range of from 24 ng to 250 xcexcg, preferably from 250 ng to 25 xcexcg, per kg bodyweight. These dosage ranges may be compared with a proposed dosage rate of from 1 to 50 mg/kg bodyweight per day with the treatments disclosed in U.S. Pat. No. 5,516,807. Thus it will be apparent that the potential risk of side effects with the present invention is very dramatically reduced relative to the prior art.
Conveniently the formulations of the present invention are presented in unit dosage form, for example, in ampoules. Typically each unit dosage formulation contains from 2 xcexcg to 12.5 mg, preferably from 20 xcexcg to 1 mg, for example, about 125 xcexcg, of the farnesyl transferase inhibitor. Conveniently each unit dosage contains from 1 to 10 ml, preferably from 2 to 5 ml, of liquid formulation.
Further preferred features and advantages of the invention will appear from the following examples given by way of illustration of the present invention, and with reference to the accompanying drawings wherein: